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Methamphetamine, HIV, Neuroinflammation and Behavior

甲基苯丙胺、艾滋病毒、神经炎症和行为

基本信息

批准号：
7499027
负责人：
Rodney W Johnson
金额：
$ 18.74万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7499027
关键词：
AIDS Dementia Complex Acquired Immunodeficiency Syndrome Address Affect Animal Model Area Attention Behavior Behavioral Brain Cells Cognition Disorders Cognitive Cognitive deficits Corpus striatum structure Daily Development Disease Dopamine Doxycycline Drug abuse Drug user Exposure to Fatigue Frequencies Glial Fibrillary Acidic Protein Goals HIV HIV Envelope Protein gp120 HIV Infections HIV-1 Hippocampus (Brain)Incidence Individual Infection Inflammation Inflammatory Injection of therapeutic agent Lead Learning Link Localized Measures Mental Depression Methamphetamine Methodology Microglia Morbidity - disease rate Motor Motor Activity Mus Neurons Numbers Patients Persons Production Proteins Reporting Research Risk Risk Behaviors Serotonin Sexually Transmitted Diseases Site Staining method Stains System Techniques Thinking Tissues Transgenic Organisms United States classical conditioning cognitive change cytokine drug of abuse experience high risk sexual behavior innovation intraperitoneal laser capture microdissection motor deficit motor learning mouse model neurobehavioral neuroinflammation neurotoxic promoter release factor response retinal rods treatment effect

项目摘要

DESCRIPTION (provided by applicant): Methamphetamine (MA) is a common drug of abuse in the United States and is associated with increased frequency of high-risk sexual behavior leading to human immunodeficiency virus type 1 (HIV-1) exposure. Infection with HIV-1 can lead to HIV-associated dementia (HAD) and other co-morbidities like fatigue and depression. It has become apparent that HIV-1 infected individuals who abuse MA are more likely to experience neurobehavioral complications than are HIV-1 infected non-users. We propose that this is because MA sensitizes cells in the brain, particularly microglia, to HIV-1 proteins. HIV-1 infects microglial cells but because neurons are not productively infected by HIV-1, the development of neurobehavioral complications is thought to be due to soluble factors released by infected or activated microglia such as inflammatory cytokines. That MA abuse may activate or sensitize microglial cells and promote neuroinflammation in HIV-1 patients is highly relevant to HAD and other AIDS co-morbidities. Thus, if MA sensitizes the brain by increasing the number of activated microglia and/or potentiating the release of inflammatory cytokines and neurotoxic products in response to HIV-1 proteins, this might explain why infected drug users are more likely to develop neurobehavioral complications than infected non-users. Unfortunately, the relationship between MA abuse, neuroinflammation, and HAD and other AIDS co-morbidities has not been explored. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state. In the first aim, mice sensitized to MA through daily i.p. injections will be injected i.c.v. with vehicle or HIV-1 gp120 and the cognitive effects of MA and gp120 will be explored by utilizing two different learning paradigms: a) an associative learning task that is considered striatal-dependent; and b) a spatial learning task that is considered hippocampal-dependent. This methodology allows for the delineation of cognitive changes that may occur due to alterations in these discrete brain areas. Furthermore, motor learning and coordination will be assessed on a Rota-rod. Similar studies will be conducted using a Tat transgenic mouse model in which targeted Tat expression is linked to a doxycycline-inducible GFAP promoter. The second aim will determine if MA sensitization exacerbates the production of inflammatory cytokines after exposure to HIV proteins. Inflammatory cytokines will be measured in hippocampal and striatal tissue obtained using laser capture microdissection techniques; and cytokine-positive microglia will be localized by immunohistochemical staining. Special attention is paid to the striatum because MA alters motor activity by inducing dopamine release at this site, and the hippocampus because it is densely populated with microglia and is involved in cognitive disorders that are evident in patients with HAD. In addition to inflammatory cytokines, treatment effects on the dopaminergic and serotoninergic systems will be measured. The proposed studies are critically needed to understand the insidious relationship between drug abuse, HIV-1 infection, and HAD. Methamphetamine abuse is associated with increased frequency of high-risk sexual behavior leading to HIV-1 exposure and it has become apparent that HIV-1 infected individuals who abuse MA are likely to experience more severe cognitive and motor complications than are non-users which may be due to an increase in neuroinflammation. Given the increasing number of HIV-1 infected persons that also abuse MA, a better understanding of how MA influences the neurobehavioral complications associated with HIV-1 infection is needed. Therefore, the goal of this proposal is to investigate if MA use and HIV-1 infection unite to exacerbate the cognitive and motor complications associated with HIV disease and produce a heightened neuroinflammatory state.

描述（由申请人提供）：甲基苯丙胺（MA）在美国是一种常见的滥用药物，与导致人类免疫缺陷病毒1型（HIV-1）暴露的高危性行为频率增加有关。感染HIV-1可导致hiv相关痴呆（HAD）和其他合并症，如疲劳和抑郁。很明显，滥用MA的HIV-1感染者比不使用MA的HIV-1感染者更容易出现神经行为并发症。我们认为这是因为MA使大脑中的细胞，特别是小胶质细胞对HIV-1蛋白敏感。HIV-1感染小胶质细胞，但由于神经元不会被HIV-1有效感染，神经行为并发症的发生被认为是由于感染或激活的小胶质细胞释放的可溶性因子，如炎症细胞因子。MA滥用可能激活或致敏小胶质细胞，促进HIV-1患者的神经炎症，这与HAD和其他艾滋病合并症高度相关。因此，如果MA通过增加激活的小胶质细胞的数量和/或增强炎症细胞因子和神经毒性产物的释放来对HIV-1蛋白作出反应，从而使大脑变得敏感，这可能解释了为什么受感染的吸毒者比受感染的非吸毒者更容易出现神经行为并发症。不幸的是，MA滥用、神经炎症、HAD和其他艾滋病合并症之间的关系尚未被探讨。因此，本研究的目的是研究MA的使用和HIV-1感染是否会加剧与HIV疾病相关的认知和运动并发症，并产生更高的神经炎症状态。在第一个目标中，通过每日i.p.注射对MA敏感的小鼠将被注射载体或HIV-1 gp120，并通过使用两种不同的学习范式来探索MA和gp120的认知作用：a)被认为是纹状体依赖的联想学习任务；b)一个空间学习任务被认为是海马体依赖的。这种方法允许描述由于这些分散的大脑区域的改变而可能发生的认知变化。此外，运动学习和协调将在旋转棒上进行评估。类似的研究将使用Tat转基因小鼠模型进行，其中靶向Tat表达与强力霉素诱导的GFAP启动子相关联。第二个目的是确定暴露于HIV蛋白后，MA致敏是否会加剧炎症细胞因子的产生。使用激光捕获显微解剖技术测量海马和纹状体组织中的炎症细胞因子；细胞因子阳性的小胶质细胞将通过免疫组织化学染色进行定位。我们特别关注纹状体，因为MA通过在该部位诱导多巴胺释放来改变运动活动，而海马体则因为它密集分布着小胶质细胞，与HAD患者明显的认知障碍有关。除炎性细胞因子外，还将测量对多巴胺能和血清素能系统的治疗效果。拟议的研究是迫切需要了解药物滥用，HIV-1感染和HAD之间的潜在关系。甲基苯丙胺滥用与导致艾滋病毒-1暴露的高风险性行为频率增加有关，而且很明显，滥用甲基苯丙胺的艾滋病毒-1感染者可能比不使用甲基苯丙胺的人出现更严重的认知和运动并发症，这可能是由于神经炎症增加。鉴于越来越多的HIV-1感染者也滥用MA，需要更好地了解MA如何影响与HIV-1感染相关的神经行为并发症。因此，本研究的目的是研究MA的使用和HIV-1感染是否会加剧与HIV疾病相关的认知和运动并发症，并产生更高的神经炎症状态。